Adamantane derivatives, processes for their preparation and pharmaceutical composition containing them

ABSTRACT

The invention provides compounds of formula 
                         
in which m, n, R 1 , R 2 , R 3 , R 4 , and R 5 , have the meanings defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/SE2004/000227, filed Feb. 19, 2004, which claims the benefit ofSwedish Patent Application Serial No. 0300480-1, filed Feb. 21, 2003.The contents of both applications are hereby incorporated by referencein their entireties.

The present invention relates to adamantane derivatives, processes fortheir preparation, pharmaceutical compositions containing them, aprocess for preparing the pharmaceutical compositions, and their use intherapy.

The P2X₇ receptor (previously known as P2Z receptor), which is aligand-gated ion channel, is present on a variety of cell types, largelythose known to be involved in the inflammatory/immune process,specifically, macrophages, mast cells and lymphocytes (T and B).Activation of the P2X₇ receptor by extracellular nucleotides, inparticular adenosine triphosphate, leads to the release ofinterleukin-1β (IL-1β) and giant cell formation (macrophages/microglialcells), degranulation (mast cells) and proliferation (T cells),apoptosis and L-selectin shedding (lymphocytes). P2X₇ receptors are alsolocated on antigen-presenting cells (APC), keratinocytes, salivaryacinar cells (parotid cells), hepatocytes and mesangial cells.

It would be desirable to make compounds effective as P2X₇ receptorantagonists for use in the treatment of inflammatory, immune orcardiovascular diseases, in the aetiologies of which the P2X₇ receptormay play a role.

In accordance with the present invention, there is therefore provided acompound of formula

-   wherein m represents 1, 2 or 3, preferably 1 or 2;-   each R¹ independently represents a hydrogen or halogen (e.g.    fluorine, chlorine, bromine or iodine) atom, preferably a hydrogen    atom;-   one of R² and R³ represents halogen, nitro, amino, hydroxyl, or a    group selected from (i) C₁–C₆ alkyl optionally substituted by at    least one halogen atom, (ii) C₃–C₈ cycloalkyl, (iii) C₁–C₆ alkoxy    optionally substituted by at least one halogen atom, and (iv) C₃–C₈    cycloalkyloxy, and the other of R² and R³ represents a hydrogen or    halogen atom;-   n represents 0, 1 or 2; and-   R⁴ and R⁵ each independently represent a hydrogen atom or a C₁–C₆    alkyl group optionally substituted by at least one substituent    selected from hydroxyl, halogen and C₁–C₆ alkoxy;    or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, unless otherwise indicated,an alkyl substituent or alkyl moiety in a substituent group may belinear or branched. Examples of alkyl groups/moieties containing up to 6carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl and n-hexyl. Further, it should beappreciated that if R⁴ and/or R⁵ represents a C₁–C₆ alkyl groupsubstituted by at least one substituent being a hydroxyl or C₁–C₆ alkoxygroup, the hydroxyl or alkoxy substituent will not be attached to thecarbon atom which is adjacent to the nitrogen atom.

One of R² and R³ represents a halogen (e.g. fluorine, chlorine, bromineor iodine), nitro, amino (—NH₂), hydroxyl, or a group selected from (i)C₁–C₆ alkyl, preferably C₁–C₄ alkyl, optionally substituted by at leastone (e.g. one, two, three or four) halogen atom(s) as defined above,(ii) C₃–C₈ cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl), (iii) C₁–C₆ alkoxy, preferably C₁–C₄ alkoxy, optionallysubstituted by at least one (e.g. one, two, three or four) halogenatom(s) as defined above, and (iv) C₃–C₈ cycloalkyloxy (e.g.cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), and theother of R² and R³ represents a hydrogen or halogen atom as definedabove.

In one embodiment of the invention, one of R² and R³ represents ahalogen (such as a chlorine or bromine) atom and the other of R² and R³represents a hydrogen atom.

In an embodiment of the invention, m is 1.

In another embodiment of the invention, R³ represents a hydrogen atom.

In another embodiment of the invention, n is 1.

In a further embodiment of the invention, n is 1 and the compound offormula (I) has the following stereochemistry:

R⁴ and R⁵ each independently represent a hydrogen atom or a C₁–C₆, forexample, C₁–C₄ or C₁–C₃, alkyl group which may be optionally substitutedby at least one substituent (e.g. one, two, three or four substituentsindependently) selected from hydroxyl, halogen (e.g. fluorine, chlorine,bromine or iodine) and C₁–C₆, for example, C₁–C₄, alkoxy (e.g. methoxy,ethoxy, n-propoxy, n-butoxy, n-pentoxy and n-hexoxy.

In an embodiment of the invention, R⁴ and R⁵ each independentlyrepresent a hydrogen atom or a C₁–C₆ alkyl group which may be optionallysubstituted by at least one, e.g. one or two, hydroxyl group(s).

In another embodiment of the invention, R⁴ and R⁵ each independentlyrepresent a hydrogen atom or a group selected from —CH₃, —C₂H₅,—CH(CH₃)₂, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —CH(CH₃)CH₂OH, —CH₂CH(CH₃)OH,—CH₂CH(OH)CH₃, —CH₂CH(OH)CH₂OH, —CH₂C(CH₃)₂OH, —CH(isopropyl)CH₂OH,—CH(CH₂OH)₂, or —CH₂C(CH₃)₂CH₂OH.

In a further embodiment of the invention, R⁴ and R⁵ each independentlyrepresent a hydrogen atom or a group selected from —CH₃, —C₂H₅,—CH(CH₃)₂ and —(CH₂)₃OH.

In an embodiment of the invention, there is provided a subset ofcompounds of formula (I), and pharmaceutically acceptable salts andsolvates thereof, in which:

-   m represents 1;-   each R¹ represents a hydrogen atom;-   one of R² and R³ represents a halogen atom, and the other of R² and    R³ represents a hydrogen atom;-   n is 0, 1 or 2; and-   R⁴ and R⁵ each independently represent a hydrogen atom or a group    selected from —CH₃, —C₂H₅, —CH(CH₃)₂ and, —(CH₂)₃OH.

In another embodiment of the invention, there is provided a furthersubset of compounds of formula (I), and pharmaceutically acceptablesalts and solvates thereof, in which:

-   m represents 1;-   each R¹ represents a hydrogen atom;-   one of R² and R³ represents a halogen atom, and the other of R² and    R³ represents a hydrogen atom;-   n is 0, 1 or 2; and-   one of R⁴ and R⁵ represents a hydrogen atom or —CH₃ and the other of    R⁴ and R⁵ represents a group selected from —CH₃, —C₂H₅, —CH(CH₃)₂    and —(CH₂)₃OH.

Examples of compounds of the invention include:

-   -   2-Chloro-5-[(3S)-3-hydroxy-4-(methylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,    -   2-Chloro-5-[(3S)-3-hydroxy-4-(ethylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,    -   2-Chloro-5-[(3S)-3-hydroxy-4-(1-methylethylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,    -   2-Chloro-5-[(3R)-3-hydroxy-4-(methylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,    -   2-Chloro-5-[(2R)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide        hydrochloride,    -   2-Chloro-5-[(2R)-2-hydroxy-3-[(1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.13^(3,7)dec-1-ylmethyl)-benzamide        hydrochloride,    -   2-Chloro-5-[(2R)-2-hydroxy-3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide        hydrochloride,    -   2-Chloro-5-[(2R)-3-(dimethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide        hydrochloride,    -   2-Chloro-5-[(1S)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide        hydrochloride,    -   2-Chloro-5-[(1R)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide        hydrochloride,    -   2-Chloro-5-[(1R)-2-(ethylamino)-1-hydroxyethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,    -   2-Chloro-5-[(1R)-1-hydroxy-2-[(3-hydroxypropyl)amino]ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,    -   2-Chloro-5-[(2S)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide        hydrochloride,    -   2-Chloro-5-[(2S)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide        hydrochloride,    -   2-Chloro-5-[(2R)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide        benzoic acid salt,        and all pharmaceutically acceptable salts and solvates of any        one thereof.

The present invention further provides a process for the preparation ofa compound of formula (I) as defined above, or a pharmaceuticallyacceptable salt or solvate thereof, which comprises:

-   (i) when n is 0, reacting a compound of formula

-    wherein m, R¹, R² and R³ are as defined in formula (I), with a    compound of formula (III), HNR⁴R⁵, wherein R⁴ and R⁵ are as defined    in formula (I); or-   (ii) when n is 1, reacting a compound of formula

-    wherein m, R¹, R² and R³ are as defined in formula (I), with a    compound of formula (III) as defined in (i) above; or-   (iii) when n is 2, reacting a compound of formula

-    wherein L¹ is a leaving group (e.g. halogen, nitrobenzenesulfonyl,    methanesulfonyl or an alternative leaving group for nucleophilic    displacement reactions) and m, R¹, R² and R³ are as defined in    formula (I), with a compound of formula (III) as defined in (i)    above; or-   (iv) when n is 1, reacting a compound of formula

-    wherein L² is a leaving group (e.g. halogen, nitrobenzenesulfonyl,    methanesulfonyl or an alternative leaving group for nucleophilic    displacement reactions) and m, R¹, R² and R³ are as defined in    formula (I), with a compound of formula (III) as defined in (i)    above;-   and optionally after (i), (ii) (iii) or (iv) carrying out one or    more of the following:    -   converting the compound obtained to a further compound of        formula (I)    -   forming a pharmaceutically acceptable salt or solvate of the        compound.

In process (i), the compound of formula (II) may be convenientlysynthesised by reacting a compound of formula

wherein L³ represents a leaving group (e.g. halogen, phosphate,trifluoromethane sulphonate or an alternative leaving group for metalcatalysed coupling reactions) and m, R¹, R² and R³ are as defined informula (I), with a compound of formula

wherein L⁴ represents a leaving group (e.g. trialkyltin, boronic acid oran alternative leaving group for metal catalysed coupling reactions)under metal catalysed coupling conditions such astetrakis(triphenylphosphine)palladium(0).

The subsequent oxidation reaction may be performed with a reagent suchas m-chloroperbenzoic acid in a suitable solvent such asdichloromethane.

Compounds of formula (II) may also be prepared by reacting a compound offormula

wherein m, R¹, R² and R³ are as defined in formula (I), with a compoundof formula (XIII) or (XIV) suitably deprotonated by a base such assodium hydride,

Reaction of the resultant epoxide may be performed by addition of therequired amine of formula (III) at room temperature or at elevatedtemperature. An example of a compound of formula (XIII) istrimetlylsulfonium iodide.

In process (ii), the compound of formula (IV) may be convenientlysynthesised by reacting a compound of formula

wherein L⁵ represents a leaving group (e.g. halogen, phosphate,trifluoromethane sulphonate or an alternative leaving group for metalcatalysed coupling reactions) and m, R¹, R² and R³ are as defined informula (I), with a compound of formula

wherein L⁶ represents a leaving group (e.g. trialkyltin, trialkylsilane,boronate, boronic acid or an alternative leaving group for metalcatalysed coupling reactions) under metal catalysed coupling conditionssuch as dichlorobis(triphenylphosphine)palladium(II). The subsequentoxidation reaction may be performed with a reagent such asm-chloroperbenzoic acid or a combination of pyrazole,methyltrioxorhenium(VII) and hydrogen peroxide in a suitable solventsuch as dichloromethane.

Compounds of formula (IV) may also be prepared by reacting a compound offormula

wherein m, R¹, R² and R³ are as defined in formula (I), with a compoundof formula (XIII) or (XIV) as defined above suitably deprotonated by abase such as sodium hydride.

Reaction of the resultant epoxide may be performed by addition of therequired amine of formula (III) at room temperature or at elevatedtemperature.

In process (iii), the compound of formula (V) may be convenientlysynthesised by reacting a compound of formula

wherein L⁷ represents a leaving group (e.g. halogen, phosphate,trifluoromethane sulphonate or an alternative leaving group for metalcatalysed coupling reactions) and m, R¹, R² and R³ are as defined informula (I), with a compound of formula

wherein P¹ and P² each independently represent a protecting group, inthe presence of tetrakis(triphenylphosphine)palladium(0), followed byremoval of the protecting groups with a reagent such as hydrochloricacid and reaction with a reagent such as methanesulphonyl chloride.Protecting groups P¹ and P² may be selected from any of the wide rangeof hydroxyl protecting groups known in the art.

The compound of formula (V) may be reacted with the amine of formula(III) at room temperature or at elevated temperature.

In process (iv), the compound of formula (VI) may be convenientlysynthesised by reacting a compound of formula

wherein L⁸ represents a leaving group (e.g. halogen, phosphate,trifluoromethane sulphonate or an alternative leaving group for metalcatalysed coupling reactions) and m, R¹, R² and R³ are as defined informula (I) (suitably metallated with a reagent such as butyllithium orisopropylmagnesium chloride followed by addition of copper(I) bromidedimethylsulphide complex), with a compound of formula

wherein L⁹ is a leaving group (e.g. halogen, nitrobenzenesulfonyl,methanesulfonyl or an alternative leaving group for nucleophilicdisplacement reactions), followed by reaction with a reagent such asmethanesulphonyl chloride.

The compound of formula (VI) may be reacted with the amine of formula(III) at room temperature or at elevated temperature.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard procedures. For example, compounds of formula(I) in which one of R² and R³ represents a halogen atom may be convertedto a corresponding compound of formula (I) in which one of R² and R³represents a C₁–C₆ alkyl group by reaction with an alkyl Grignardreagent (e.g. methyl magnesium bromide) in the presence of a catalystsuch as [1,3-bis(diphenylphosphino)propane]dichloronickel (II) in asolvent such as tetrahydrofuran.

Compounds of formula (X), (XII), (XV), (XVII), (XVIII) referred to abovemay be prepared by known chemistry, for example by methods according oranalogous to those described in WO 99/29661 and WO 00/61569.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at various stages, the additionand removal of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate, or an alkali metal salt such as a sodium orpotassium salt.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.Enantiomerically pure forms are particularly desired.

The compounds of the present invention are advantageous in that theypossess pharmacological activity. They are therefore indicated aspharmaceuticals for use in the treatment of rheumatoid arthritis,osteoarthritis, psoriasis, allergic dermatitis, asthma, chronicobstructive pulmonary disease (COPD), hyperresponsiveness of the airway,septic shock, glomerulonephritis, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, atherosclerosis, growth and metastases ofmalignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease,meningitis, osteoporosis, bum injury, ischaemic heart disease, stroke,varicose veins, sarcoidosis, rhinitis, acute and chronic pain, multiplesclerosis, myeloma, bone loss associated with malignancy andinflammatory and neurodegenerative diseases of the eye such asscleritis, episcleritis, uveitis, Sjogrens syndrome-keratoconjuctivitis,sclerokeratitis, optic neuritis, diabetic retinopathy, retinitispigmentosa, antimalarial—induced retinopathy.

Accordingly, the present invention provides a compound of formula (I) ora pharmaceutically acceptable salt or solvate thereof as hereinbeforedefined for use in therapy.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof ashereinbefore defined in the manufacture of a medicament for use intherapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention further provides a method of effecting immunosuppression(e.g. in the treatment of rheumatoid arthritis, osteoarthritis,inflammatory bowel disease, atherosclerosis or psoriasis) whichcomprises administering a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt or solvate thereofas hereinbefore defined to a patient.

The invention also provides a method of treating an obstructive airwaysdisease (e.g. asthma or COPD) which comprises administering to a patienta therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as hereinbeforedefined to a patient.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I)/salt/solvate (active ingredient) may be inthe range from 0.001 mg/kg to 30 mg/kg.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.10 to 70% w, of active ingredient, and, from 1 to99.95% w, more preferably from 30 to 99.90% w, of a pharmaceuticallyacceptable adjuvant, diluent or carrier, all percentages by weight beingbased on total composition.

Thus, the present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof as hereinbefore defined with a pharmaceutically acceptableadjuvant, diluent or carrier.

The pharmaceutical composition of the invention may be administeredtopically (e.g. to the lung and/or airways or to the skin) in the formof solutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules, or by parenteraladministration in the form of solutions or suspensions, or bysubcutaneous administration or by rectal administration in the form ofsuppositories or transdermally.

The invention further relates to combination therapies for the treatmentof any one of rheumatoid arthritis, osteoarthritis, osteoporosis,psoriasis, inflammatory bowel diseases, COPD, asthma, allergic rhinitisor cancer or the neurodegenerative diseases such as multiple sclerosis,Alzheimer's disease or stroke. For the treatment of rheumatoidarthritis, the compounds of the invention may be combined with“biological agents” such as TNF-α inhibitors such as anti-TNF monoclonalantibodies (such as Remicade, CDP-870 and Humira) and TNF receptorimmunoglobulin molecules (such as Enbrel.reg.). IL-1 receptor antagonist(such as Anakinra) and IL-1 trap, IL-18 receptor, anti-IL-6 Ab,anti-CD20 Ab, anti-IL-15 Ab and CTLA4Ig.

Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin. The COX-2 inhibitors (such as meloxicam,celecoxib, rofecoxib, valdecoxib and etoricoxib) and the cylco-oxygenaseinhibiting nitric oxide donors (CINOD's) and the “disease modifyingagents” (DMARDs) such as methotrexate, sulphasalazine, cyclosporine A,lefimomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofinor parenteral or oral gold.

The present invention still her relates to the combination of a compoundof the invention together with a leukotriene biosynthesis inhibitor,5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein(FLAP) antagonist selected from the group consisting of zileuton;ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compoundSB-210661; pyridinyl-substituted 2n cyanonaphthalene compounds such asL-739,010; 2-cyanoquinoline compounds such as L-746,530; indole andquinoline compounds such as MK-591, MK-886, and BAY x 1005.

The present invention still further relates to the combination of acompound of the invention together with a receptor antagonists forleukotrienes LTB₄, LTC₄, LTD₄, and LTE₄ selected from the groupconsisting of the phenothiazin-3-ones such as L-651,392; amidinocompounds such as CGS-25019c; benzoxalamines such as ontazolast;benzenecarboximidamides such as BIIL 284/260; and compounds such aszafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention together with a PDE4 inhibitor includinginhibitors of the isoform PDE4D.

The present invention still further relates to the combination of acompound of the invention together with a antihistaminic H₁ receptorantagonists including cetirizine, loratadine, desloratadine,fexofenadine, asterizole, azelastine, and chlorpheniramine.

The present invention still further relates to the combination of acompound of the invention together with a gastroprotective H₂ receptorantagonist or the proton pump inhibitors (such as omeprazole)

The present invention still further relates to the combination of acompound of the invention together with an α₁- and α₂-adrenoceptoragonist vasoconstrictor sympathomimetic agent, includingpropylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, and ethylnorepinephrinehydrochloride.

The present invention still further relates to the combination of acompound of the invention together with anticholinergic agents includingipratropium bromide; tiotropium bromide; oxitropium bromide;pirenzepine; and telenzepine.

The present invention still further relates to the combination of acompound of the invention together with β₁- to β₄-adrenoceptor agonistsincluding metaproterenol isoproterenol, isoprenaline, albuterol,salbutamol, formoterol, salmeterol, terbutaline, orciprenaline,bitolterol mesylate, and pirbuterol; or methylxanthanines includingtheophylline and aminophylline; sodium cromoglycate; or muscarinicreceptor (M1, M2, and M3) antagonist.

The present invention still further relates to the combination of acompound of the invention together with other modulators of chemokinereceptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1,CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CR1 for the C-X₃-Cfamily.

The present invention still further relates to the combination of acompound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination ofcompound of the invention together with an inhaled glucocorticoid withreduced systemic side effects, including prednisone, prednisolone,flunisolide, triamcinolone acetonide, beclomethasone dipropionate,budesonide, fluticasone propionate, and mometasone furoate.

The present invention still further relates to the combination of acompound of the invention together with (a) tryptase inhibitors; (b)platelet activating factor (PAF) antagonists; (c) interleukin convertingenzyme (ICE) inhibitors; (d) IMPDH inhibitors; (e) adhesion moleculeinhibitors including VLA-4 antagonists; (f) cathepsins; (g) MAP kinaseinhibitors; (h) glucose-6 phosphate dehydrogenase inhibitors; (i)kinin-B₁- and B₂-receptor antagonists; (j) anti-gout agents, e.g.,colchicine; (k) xanthine oxidase inhibitors, e.g., allopurinol; (I)uricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbropmarone;(m) growth hormone secretagogues; (n) transforming growth factor (TGFβ);(o) platelet-derived growth factor (PDGF); (p) fibroblast growth factor,e.g., basic fibroblast growth factor (bFGF); (q) granulocyte macrophagecolony stimulating factor (GM-CSF); (r) capsaicin cream; (s) TachykininNK₁ and NK₃ receptor antagonists selected from the group consisting ofNKP-608C; SB-233412 (talnetant); and D-4418; and (t) elastase inhibitorsselected from the group consisting of UT-77 and ZD-0892 (u) inducednitric oxide synthase inhibitors (iNOS) or (v) chemoattractantreceptor-homologous molecule expressed on TH2 cells, (CRTH2antagonists).

The present invention still further relates to the combination of acompound of the is invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11).

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, induced nitric oxide synthase inhibitors(iNOS inhibitors), COX-2 inhibitors such as celecoxib, valdecoxib,rofecoxib and etoricoxib, and the cylco-oxygenase inhibiting nitricoxide donors (CINOD's) analgesics (such as paracetamol and tramadol),cartilage sparing agents such as diacerein, doxycyline and glucosamine,and intra-articular therapies such as corticosteroids and hyaluronicacids such as hyalgan and synvisc.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of inflammatory boweldiseases (Ulcerative colitis and Crohn's disease). Suitable agents to beused include sulphasalazine, 5-amino-salicylates, the thiopurines,azathioprine and 6-mecaptorurine and corticosteroids such as budesonide.

The compounds of the present invention may also be used in combinationwith anticancer agents such as endostatin and angiostatin or cytotoxicdrugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol,taxotere and farnesyl transferase inhibitors, VegF inhibitors, COX-2inhibitors and antimetabolites such as methotrexate, antineoplasticagents, especially antimitotic drugs including the vinca alkaloids suchas vinblastine and vincristine.

The compounds of the invention may also be used in combination withantiviral agents such as Viracept, AZT, aciclovir and famciclovir, andantisepsis compounds such as Valant.

The compounds of the present invention may also be used in combinationwith cardiovascular agents such as calcium channel blockers, lipidlowering agents such as statins, fibrates, beta-blockers, Aceinhibitors, Angiotensin-2 receptor antagonists and platelet aggregationinhibitors.

The compounds of the present invention may also be used in combinationwith CNS agents such as antidepressants (such as sertraline),anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOBinhibitors such as selegine and rasagiline, comp inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitricoxide synthase), and anti Alzheimer's drugs such as donepezil, tacrine,COX-2 inhibitors, propentofylline or metryfonate.

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, droloxifene, lasofoxifeneor fosomax and immunosuppressant agents such as FK-506, rapamycin,cyclosporine, azathioprine, and methotrexate.

The present invention will now be further explained by reference to thefollowing illustrative examples. In the examples the NMR spectra weremeasured on a Varian Unity spectrometer at a proton frequency of either300 or 400 MHz. The MS spectra were measured on either a Agilent 1100MSD G1946D spectrometer or a Hewlett Packard HP1100 MSD G1946Aspectrometer. Preparative HPLC separations were performed using aWaters' Symmetry™ or Xterra™ column or a Novapak™ column.

EXAMPLE 12-Chloro-5-[(3S)-3-hydroxy-4-(methylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,hydrochloride

a) 5-Ethenyl-2,2,3,3,8,8,9,9-octamethyl-(5S) 4,7-dioxa-3,8-disiladecane

Imidazole (4 g) was added portionwise to a solution of(2S)-3-butene-1,2-diol (2 g) andchloro(1,1-dimethylethyl)dimethyl-silane (7 g) in N,N-dimethylformamide(20 mL). The mixture was stirred at room temperature for 24 hours. Thebiphasic reaction mixture was poured into ether and washed with water(×3) and brine, dried over anhydrous magnesium sulfate, filtered andevaporated, to give an oil (7.5 g). Purification by bulb-bulbdistillation (130–150° C. at 3 mm Hg), gave the sub-titled compound asan oil (5.3 g).

¹H NMR (300 MHz, CDCl₃) δ 5.92–5.81 (1H, m), 5.26 (1H, d), 5.11 (1H, d),4.16 (1H, q), 3.57–3.42 (2H, m), 0.90 (18H, s), 0.05 (12 H,s).

b)2-Chloro-5-[(3S)-3,4-dihydroxybutyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

9-Borabicyclo[3.3.1]nonane dimer (1.8 g) was added at room temperatureto a solution of 5-ethenyl-2,2,3,3,8,8,9,9-octamethyl-(5S)4,7-dioxa-3,8-disiladecane (Example 1 a) (1.0 g) in tetrahydrofuran (20mL), under nitrogen. N,N-dimethylformamide (20 mL) was added to thereaction mixture and degassed by bubbling nitrogen through the reactionmixture for 30 minutes. A solution of2-chloro-5-iodo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide (1.3g) (prepared as described in WO99/29661) in N,N-dimethylformamide (10mL) was added to the reaction mixture and degassing continued for 45min. Potassium carbonate (1.0 g) andtetrakis(triphenylphosphine)palladium(0) (0.2 g) were added to thereaction mixture and heated to 80–90° C. for 24 hours under nitrogen. Oncooling to room temperature the reaction mixture was poured into ethylacetate and the organic layer washed with water, aqueous hydrochloricacid (2M), brine, dried over anhydrous magnesium sulfate, filtered andevaporated. The resulting oil was redissolved in dichloromethane (50 mL)and hydrochloric acid in 1,4-dioxane (4M, 5 mL) was added. After 18hours the reaction mixture was concentrated and purified by columnchromatography (gradient 0–5% methanol in dichloromethane). Furtherpurification by reverse phase HPLC (gradient 25–95% acetonitrile (MeCN)in 0.2% aqueous ammonium acetate (NH₄AcO) on Symmetry™ column) gave thesub-titled product as a white solid (0.36 g).

¹H NMR (300 MHz, CDCl₃) δ 7.57 (1H, d), 7.31 (1H, d), 7.20 (1H, dd),6.30 (1H, s), 3.76–3.56 (2H, m), 3.46 (1H, t), 3.18 (2H, d), 2.87–2.66(2H, m), 2.34 (1H, s), 2.07–1.91 (4H, m), 1.80–1.54 (14H, m).

MS (APCI+) ion [M+H]⁺ 392/4

m.p. 145–147° C.

[α]_(D) ²⁵ (C=0.16 in MeOH) −16.4°

c)2-Chloro-5-[(3S)-3-hydroxy4-[(methylsulfonyl)oxy]butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

Methanesulfonylchloride (0.08 mL) was added to a solution of2-chloro-5-[(3S)-3,4-dihydroxybutyl]-N-(tricyclo(3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide(Example 1b) (0.33 g) and triethylamine (0.33 ml) in dichloromethane (10mL). After 1 hour the reaction mixture was concentrated, redissolved inethyl acetate and the organic layer washed with water, brine, dried overanhydrous magnesium sulfate, filtered and evaporated. Purification bynormal phase HPLC (gradient 0–5% ethanol (EtOH) in dichloromethane onsilica Novapak™ column), gave the sub-titled compound (0.14 g).

¹H NMR (300 MHz, CDCl₃) δ 7.57 (1H, d), 7.33 (1H, d), 7.20 (1H, dd),6.31 (1H, s), 4.25–4.09 (2H, m), 3.96–3.81 (1H, m), 3.18 (2H, d), 3.06(3H, s), 2.93–2.65 (2H, m), 2.30 (1H, d), 2.01 (3H, s), 1.87–1.57 (14H,m).

MS (APCI+) ion [M+H]⁺ 470/2

d)2-Chloro-5-[(3S)-3-hydroxy-4-(methylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

Aqueous methylamine (40%) (3 mL) was added to a solution of2-chloro-5-[(3S)-3-hydroxy-4-[(methylsulfonyl)oxy]butyl]-N-(tricyclo[3.3.1.1^(3,7)dec-1-ylmethyl)benzamide(Example 1c) (0.13 g) in acetonitrile (20 mL) and heated at 50° C. for 4hours. Further aqueous methylamine (40%) (2 mL) was added and heating at50° C. continued for a further 1 hour. On cooling the reaction mixturewas concentrated and purified by solid phase extraction on Waters' SCXresin, eluting with ammonia in methanol (7M). The residue was dissolvedin methanol (5 mL) and hydrochloric acid in dioxane (4M, 1 mL) wasadded, evaporation gave the titled compound (0.12 g).

¹H NMR (300 MHz, d₆-DMSO) δ 8.69–8.37 (2H, m), 8.29 (1H, t), 7.39 (1H,d), 7.31–7.22 (2H, m), 5.60–5.21 (1H, m), 3.81–3.65 (1H, m), 3.07–2.88(3H, m), 2.88–2.57 (3H, m), 2.54 (3H, s), 1.95 (3H, s), 1.75–1.55 (8H,m), 1.52 (6H, s).

MS (APCI+) ion [M+H]⁺ 405/7

m.p.>200° C. dec

[α]_(D) ²¹ (C=0.15 in MeOH) −2.4°

EXAMPLE 22-Chloro-5-[(3S)-3-hydroxy-4-(ethylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,hydrochloride

Aqueous ethylamine (70%) (2 mL) was added to a solution of2-chloro-5-[(3S)-3-hydroxy-4-[(methylsulfonyl)oxy]butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide(Example 1c) (0.2 g) in acetonitrile (5 mL) and heated at 50° C. for 2.5hours. On cooling the reaction mixture was concentrated and purified bysolid phase extraction on Waters' SCX resin, eluting with ammonia inmethanol (7M). Further purification by reverse phase HPLC (gradient25–95% acetonitrile in 0.2% aqueous trifluoroacetic acid (TFA) onSymmetry™ column). The residue was dissolved in methanol (5 mL) andhydrochloric acid in 1,4-dioxane (4M, 1 mL) was added, evaporation andrecrystallisation from acetonitrile, gave the titled compound (0.13 g).

¹H NMR (300 MHz, d₆-DMSO) δ 8.74–8.32 (2H, m), 8.30 (1H, t), 7.39 (1H,d), 7.33–7.21 (2H, m), 5.46 (1H, d), 3.84–3.68 (1H, m), 3.05–2.85 (5H,m), 2.85–2.55 (3H, m), 1.94 (3H, s), 1.79–1.55 (8H, m), 1.52 (6H, s),1.19 (3H, t).

MS (APCI+) ion [M+H]⁺ 419/421

EXAMPLE 32-Chloro-5-[(3S)-3-hydroxy-4-(1-methylethylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,hydrochloride

1-Methylethylamine (3 mL) was added to a solution of2-chloro-5-[(3S)-3-hydroxy-4-[(methylsulfonyl)oxy]butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide(Example 1c) (0.22 g) in acetonitrile (10 mL) and heated at 50° C. for18 hours. On cooling the reaction mixture was concentrated and purifiedby solid phase extraction on Waters' SCX resin, eluting with ammonia inmethanol (7M). Further purification by reverse phase HPLC (gradient25–95% acetonitrile in 0.2% aqueous trifluoroacetic acid on Symmetry™column). The residue was dissolved in methanol (5 mL) and hydrochloricacid in dioxane (4M, 1 mL) was added, evaporation and recrystallisationfrom MeCN, gave the titled compound as the hydrochloric acid salt (30mg).

¹H NMR (300 MHz, d₆-DMSO) δ 8.70–8.21 (3H, m), 7.40 (1H, d), 7.30–7.25(2H, m), 5.44 (1H, d), 3.83–3.67 (1H, m), 3.38–3.19 (1H, m), 3.05–2.86(3H, m), 2.87–2.55 (3H, m), 1.93 (3H, s), 1.77–1.47 (14H, m), 1.24 (3H,d), 1.22 (3H, d).

MS (APCI+) ion [M+H]⁺ 433/435

EXAMPLE 42-Chloro-5-[(3R)-3-hydroxy4-(methylamino)butyl]-N-tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

a) 5-Ethenyl-2,2,3,3,8,8,9,9-octamethyl-(5R) 4,7-dioxa-3,8-disiladecane

The sub-titled compound was prepared by the method of Example 1(a) using(2R)-3-butene-1,2-diol.

¹H NMR (300 MHz, CDCl₃) δ 5.92–5.81 (1H, m), 5.26 (1H, d), 5.11 (1H, d),4.16 (1H, q), 3.57–3.42 (2H, m), 0.90 (18H, s), 0.05 (12H, s).

b)2-Chloro-5-[(3R)-3,4-dihydroxybutyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

The sub-titled compound was prepared by the method of Example 1(b) using5-ethenyl-2,2,3,3,8,8,9,9-octamethyl-(5R) 4,7-dioxa-3,8-disiladecane(product of Example 4a).

¹H NMR (300 MHz, CDCl₃) δ 7.57 (1H, d), 7.31 (1H, d), 7.20 (1H, dd),6.30 (1H, s), 3.76–3.56 (2H, m), 3.46 (1H, t), 3.18 (2H, d), 2.87–2.66(2H, m), 2.44 (1H, s), 2.07 (1H, s), 2.01 (3H, s), 1.80–1.54 (14H, m).

MS (APCI+) ion [M+H]⁺ 392/4

[α]_(D) ²⁴ (C=0.26 in MeOH)+14.0°

c) 2-Chloro-5-[(3R)-3-hydroxy-4-[(methylsulfonyl)oxy]butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

The sub-titled compound was prepared by the method of Example 1(c) using2-chloro-5-[(3R)-3,4-dihydroxybutyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide.

¹H NMR (300 MHz, CDCl₃) δ 7.57 (1H, d), 7.33 (1H, d), 7.20 (1H, dd),6.31 (1H, s), 4.25–4.09 (2H, m), 3.96–3.81 (1H, m), 3.18 (2H, d), 3.06(3H, s), 2.93–2.65 (2H, m), 2.40 (1H, s), 2.01 (3H, s), 1.87–1.57 (14H,m).

MS (APCI+) ion [M+H]⁺ 470/2

d)2-Chloro-5-[(3R)-3-hydroxy-4-(methylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

The titled compound was prepared by the method of Example 1(d) using2-chloro-5-[(3R)-3-hydroxy-4-[(methylsulfonyl)oxy]butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide.

¹H NMR (300 MHz, DMSO) δ 8.69–8.37 (2H, m), 8.29 (1H, t), 7.39 (1H, d),7.31–7.22 (2H, m), 5.60–5.21 (1H, m), 3.81–3.65 (1H, m), 3.07–2.88 (3H,m), 2.88–2.57 (3H, m), 2.54 (3H, s), 1.95 (3H, s), 1.75–1.55 (8H, m),1.52 (6H, s).

MS (APCI+) ion [M+H]⁺ 405/7

EXAMPLE 52-Chloro-5-[(2R)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,hydrochloride

a)2-Chloro-5-(2-propenyl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide

2-Chloro-5-iodo-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(prepared as described in WO 99/29661) (7.74 g), tri-n-butylallyltin(5.99 g), dichlorobis(triphenylphosphine)palladium(II) (1.24 g),triphenylphosphine (1.86 g), lithium chloride (6.11 g) andN,N-dimethylformamide. (260 mL) were heated together under nitrogen from110° C. to 130° C. over 20 minutes, and then at 130° C. for 25 minutes.The mixture was then cooled, poured into brine (500 mL), extracted intoethyl acetate (3×250 mL), dried over anhydrous magnesium sulfate,filtered and concentrated to give an oil. The crude mixture was purifiedby column chromatography eluting with 9:1 isohexane/ethyl acetate togive the sub-titled compound (5.23 g).

¹H NMR (300 MHz, CDCl₃) δ 7.54 (1H, s), 7.33–7.31 (1H, d), 7.20–7.16(1H, d), 6.25 (1H, br s), 5.99–5.85 (1H, m), 5.13–5.06 (2H, m),3.39–3.37 (2H, d), 3.19–3.17 (2H, d), 2.01 (3H, br s), 1.76–1.63 (6H, brAB), 1.58 (6H, br s).

MS (ES+) ion [M+H]⁺ 344, 346

b)2-Chloro-5-(oxiranylmethyl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide

2-Chloro-5-(2-propenyl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 5a) (9.4 g), pyrazole (0.45 g) and methyltrioxorhenium(VII)(0.40 g) were stirred together in dichloromethane (40 mL) undernitrogen, and hydrogen peroxide (27.5% wt. solution in water, 13 mL) wasadded dropwise. The reaction was then monitored by HPLC/MS and furtherportions of pyrazole, methyltrioxorhenium(VII) and hydrogen peroxidewere added over a period of 2 days until the reaction mixture consistedof a 1:1 mixture of starting material and product. The mixture was thenpoured into water (500 mL), extracted into dichloromethane (3×300 mL),washed with 2M aqueous hydrochloric acid (300 mL), brine (300 mL),saturated aqueous sodium thiosulfate (300 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated to give an oil. This waspurified by column chromatography eluting with 2:1 isohexane/ethylacetate to give the sub-titled compound (4.71 g).

¹H NMR (300 MHz, CDCl₃) δ 7.60 (1H, d), 7.38–7.34 (1H, d), 7.28–7.25(1H, dd), 6.28 (1H, br t), 3.22–3.18 (2H, d), 3.17–3.11 (1H, m),2.86–2.79 (3H, m), 2.53–2.52 (1H, m), 2.01 (3H, br s), 1.75–1.64 (6H, brAB), 1.59 (6H, br s).

MS (ES+) ion [M+H]⁺ 360, 362

c)2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide

(1R,2R)-(−)-N,N′-Bis(3,5-di-t-butylsalicydene)-1,2-cyclohexanediaminocobalt(II)(0.30 g), acetic acid (0.15 mL) and toluene (3 mL) were stirred togetherin air for 1.25 hours. The solvents were then removed in vacuo and theresultant brown glass was dried under high vaccum for 2 hours.2-Chloro-5-(oxiranylmethyl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 5b) (1.14 g), water (1.5 mL) and tetrahydrofuran (100 mL) werethen added to this and the mixture stirred under nitrogen for 82 hours,concentrated and purified by column chromatography eluting with 2:1isohexane/ethyl acetate to give the sub-titled compound (0.28 g).

MS (ES+) ion [M+H]⁺ 360, 362

d)2-Chloro-5-[(2R)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,hydrochloride salt

2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 5c) (452mg), ethylamine (70% aqueous solution, 5 mL) andtetrahydrofuiran (15 mL) were heated together at 50° C. under nitrogenfor 20 hours, cooled and concentrated to give an oil. This was purifiedby Waters' MCX resin (mixed-mode cation exchanger) and then by columnchromatography eluting with 19:1:0.1 dichloromethane/methanol/ammonia.The oil obtained was dissolved in dichloromethane (5 mL) and one molar(1M) ethereal hydrogen chloride (4 mL) was added. The mixture wasconcentrated to give the sub-titled compound as a solid (415 mg).

¹H NMR (400 MHz, d₆-DMSO) δ 8.29–8.26 (1H, t); 7.43–7.40 (1H, d);7.30–7.28 (2H, m); 5.53–5.52 (1H, d); 3.98 (2H, br m); 2.94–2.82 (5H,m); 2.79–2.67 (3H, m); 1.94 (3H, br s); 1.69–1.58 (6H, br AB); 1.52 (6H,br s); 1.20–1.16 (3H, t).

MS: APCI(+ve) ion [M+H]⁺ 405, 407

m.p. 218° C.

EXAMPLE 62-Chloro-5-[(2R)-2-hydroxy-3-[(1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,hydrochloride

2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 5c) (133 mg), isopropylamine (3 mL) and1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in asealed tube for 22 hours, cooled and poured into brine (50 mL),extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL),dried over anhydrous magnesium sulfate, filtered and concentrated togive an oil. This was purified by Waters' MCX resin and then by columnchromatography eluting with 19:1:0.1 dichloromethane/methanol/ammonia.The oil obtained was dissolved in dichloromethane (5 mL) and 1M etherealhydrogen chloride (4 mL) was added. The mixture was concentrated to givethe titled compound as a solid (85 mg).

¹H NMR (400 MHz, d₆-DMSO) δ 8.29 (1H, br t); 7.43–7.41 (1H, d);7.31–7.29 (2H, m); 5.52 (1H, br s); 3.99 (1H, br s); 2.98–2.92 (3H, m);2.83–2.67 (3H, m); 1.94 (3H, br s); 1.69–1.59 (6H, br AB); 1.23–1.20(6H, m).

MS: APCI(+ve) ion [M+H]⁺ 419, 421

m.p. 189° C.

EXAMPLE 72-Chloro-5-[(2R)-2-hydroxy-3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,hydrochloride salt

2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 5c) (133 mg), 3-amino-1-propanol (3 mL) and1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in asealed tube for 22 hours, cooled and poured into brine (50 mL),extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL),dried over anhydrous magnesium sulfate, filtered and concentrated togive an oil. This was purified by Waters' MCX resin and then by columnchromatography eluting with 9:1:0.1 dichloromethane/methanol/ammonia.This was further purified by reverse phase HPLC (gradient 25–95%acetonitrile in 0.2% aqueous trifluoroacetic acid on Xterra™ column).The oil obtained was dissolved in dichloromethane (5 mL) and 1M etherealhydrogen chloride (4 mL) was added. The mixture was concentrated to givethe titled compound as a solid (60 mg).

¹H NMR (400 MHz, d₆-DMSO) δ 8.28 (1H, br t); 7.42–7.40 (1H, d);7.30–7.28 (2H, m); 5.53 (1H, br s); 4.78 (1H, br s); 4.00 (1H, br s);3.50–3.45 (2H, br t); 3.00–2.92 (5H, m); 2.81–2.68 (3H, m); 1.94 (3H, brs); 1.76 (2H, br m); 1.69–1.58 (6H, br AB); 1.53 (6H, br s).

MS: APCI(+ve) ion [M+H]⁺ 435, 437

M.p. 225° C.

EXAMPLE 82-Chloro-5-[(2R)-3-(dimethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,hydrochloride

2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 5c) (133 mg), dimethylamine (40% solution in water, 3 mL) and1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in asealed tube for 22 hours, cooled and poured into brine (50 mL),extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL),dried over anhydrous magnesium sulfate, filtered and concentrated togive an oil. This was purified by Waters' MCX resin and then by reversephase HPLC (gradient 25–95% acetonitrile in 0.2% aqueous trifluoroaceticacid on Waters' Xterra™ column). The oil obtained was dissolved indichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) wasadded. The mixture was concentrated to give the titled compound as asolid (41 mg).

¹H NMR (400 MHz, d₆-DMSO) δ 8.29–8.26 (1H, t); 7.43–7.41 (1H, d);7.31–7.29 (2H, m); 5.64 (1H, br s); 4.11 (1H, br s); 3.15–2.98 (2H, m);2.94–2.93 (2H, d); 2.79–2.66 (7H, m); 1.94 (3H, br s); 1.69–1.58 (6H, brAB); 1.53 (6H, br s).

MS: APCI(+ve) ion [M+H]⁺ 405, 407

m.p. 198° C.

EXAMPLE 92-Chloro-5-[(1S)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamidehydrochloride

a) 2-Chloro-5-ethenyl-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

A solution of5-bromo-2-chloro-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide(prepared as described in WO 00/61569) (1.0 g),tetrakis(triphenylphosphine)palladium(0) (96 mg) and tributylvinyltin(1.15 mL) in toluene (15 mL) was heated at reflux for 3 hours, thencooled to room temperature, diluted with acetone (30 mL) and treatedwith cesium fluoride (10% aq, 10 mL) at room temperature for 2 hours.The resulting mixture was filtered through celite with further washingwith toluene and concentrated. Water was added and the mixture wasextracted with ethyl acetate. The combined organic phases were washedwith water, dried over anhydrous magnesium sulfate and concentrated. Theresulting oil was purified by column chromatography (ethylacetate:isohexane 100:1 to 80:20) to give the sub-titled compound as awhite solid (0.87 g).

¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, 1H), 7.39 (dd, 1H), 7.35 (d, 1H),6.68 (dd, 1H), 6.25 (s, 1H), 5.78 (d, 1H), 3.33 (d, 1H), 3.17 (d, 2H),2.01 (s, 3H), 1.73 (d, 3H), 1.65 (d, 3H), 1.60 (s, 6H).

b)2-Chloro-5-[(1S)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamidehydrochloride

m-Chloroperoxybenzoic acid (mCPBA) (50%, 0.44 g) was added portionwiseover 10 minutes to a solution of2-chloro-5-ethenyl-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide(Example 9a)) (0.42 g)),(S,S)-[N,N′-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminato(2-)]manganese(III)chloride (44 mg) and N-methylmorpholine (0.74 g) in dichloromethane (10mL) at −78° C. After stirring for 8 hours, a further portion of mCPBA(0.13 g) was added and the solution was left to warm slowly to roomtemperature over 16 hours. Sodium hydroxide (NaOH) (2M) was added,stirred for 1 hour and then methylamine (2M in methanol, 2 mL) wasadded. After stirring for 24 hours the reaction was concentrated,dichloromethane and water were added, the phases were separated and theaqueous was extracted with dichloromethane. The combined organic phaseswere dried over anhydrous sodium sulfate and concentrated. The resultingoil was purified by reverse phase HPLC (gradient 25–95% methanol in 1%aqueous trifluoroacetic acid). Further purification was performed bycolumn chromatography (methanol/dichloromethane/ammonia (0.88) 1:20:0.5to 15:100:0.5) gave an oil. Addition of excess 1M ethereal hydrogenchloride gave the titled compound as a white solid (158mg).

¹H NMR (400 MHz, d₆-DMSO) δ 8.33 (t, 1H), 8.20 (s, 1H), 7.48 (d, 1H),7.45 (dd, 1H), 7.40 (d, 1H), 6.20 (s, 1H), 4.91 (d, 1H), 3.25–3.40 (m,1H), 3.08 (dd, 1H), 2.95 (d, 2H), 2.85–2.95 (m, 1H), 2.55 (s, 3H), 1.95(s, 3H), 1.63 (dd, 6H), 1.52 (s, 6H).

EXAMPLE 102-Chloro-5-[(1R)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)dec-1-ylmethyl)benzamide,hydrochloride

The titled compound was prepared by the method of Example 9b) using(R,R)-[N,N′-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminato(2-)]manganese(III)chloride.

¹H NMR (400 MHz, d₆-DMSO) δ 8.55 (t, 1H), 8.34 (s, 1H), 7.49 (d, 1H),7.44 (dd, 1H), 7.40 (d, 1H), 6.26 (s, 1H), 4.93 (d, 1H), 3.26–3.40 (m,1H), 3.11 (dd, 1H), 2.95 (d, 2H), 2.95 (dd, 1H), 2.57 (s, 3H), 1.94 (s,3H), 1.64 (dd, 6H), 1.52 (s, 6H).

EXAMPLE 112-Chloro-5-[(1R)-2-(ethylamino)-1-hydroxyethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

The titled compound was prepared by the method of Example 9b) using(R,R)-[N,N′-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminato(2-)]manganese(III)chloride and ethylamine.

¹H NMR (400 MHz, d₆-DMSO) δ 8.30 (1H, t), 7.43–7.32 (3H, m), 5.40 (1H,s), 4.64 (1H, dd), 2.93 (2H, d), 2.68–2.50 (4H, m), 1.94 (3H, s), 1.63(6H, dd), 1.52 (6H, d), 1.00 (3H, t).

EXAMPLE 122-Chloro-5-[(1R)-1-hydroxy-2-[(3-hydroxypropyl)amino]ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

The titled compound was prepared by the method of Example 9b) using(R,R)-[N,N′-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminato(2-)]manganese(III)chloride and 3-aminopropan-1-ol.

¹H NMR (400 MHz, d₆-DMSO) δ 7.43–7.32 (3H, m), 5.40 (1H, s), 4.63 (1H,s), 3.44 (2H, t), 2.93 (2H, d), 2.66–2.55 (4H, m), 1.94 (3H, s), 1.64(6H, q), 1.57–1.50 (2H, m), 1.53 (6H, s).

EXAMPLE 132-Chloro-5-[(2S)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,hydrochloride

a)2-Chloro-5-(2,3-dihydroxypropyl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide

2-Chloro-5-(2-propenyl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(prepared as described in Example 5a) (1.99 g), tert-butanol (40 mL) andwater (40 mL) were stirred together under nitrogen and AD-mix-α wasadded. The mixture was then stirred at room temperature for 20 hours.Sodium sulfite (2 g) was added and the mixture was stirred for 10minutes. Water (100 mL) and ethyl acetate (100 mL) were then added. Thelayers were separated and the aqueous layer was further extracted withethyl acetate (2×100 mL). The combined extracts were dried overanhydrous magnesium sulfate, filtered and concentrated to give the crudeproduct. Purification was performed by column chromatography elutingwith 5:95 methanol/ethyl acetate to give the sub-titled compound as asolid (1.77 g).

¹H NMR (400 MHz, CDCl₃) δ 7.59 (1H, d); 7.36–7.34 (1H, d); 7.26–7.23(1H, dd); 6.29 (1H, br t); 3.98–3.91 (1H, m); 3.72–3.67 (1H, m);3.54–3.48 (1H, m); 3.18–3.17 (2H, d); 2.83–2.73 (2H, m); 2.25–2.24 (1H,d); 2.01 (3H, br s); 1.98–1.95 (1H, t); 1.75–1.64 (6H, br AB); 1.59 (6H,br s).

MS (ES+) ion [M+H]⁺ 378, 380

b)2-Chloro-5-[(2S)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide

2-Chloro-5-(2,3-dihydroxypropyl)-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 13a) (1.77 g), triethylamine (0.7 mL), dichloromethane (160 mL)and tetrahydrofuran (40 mL) were cooled to 5° C. under nitrogen andmethanesulfonyl chloride (0.35 mL) was added. The mixture was thenstirred at 5° C. for 15 minutes, poured into aqueous sodium bicarbonatesolution (75 mL), extracted into dichloromethane (3×100 mL), dried overanhydrous magnesium sulfate, filtered and concentrated to give the crudeproduct. This was purified by column chromatography eluting with ethylacetate to give the mesylate (1.06 g). The mesylate (971 mg) in methanol(45 mL) was stirred under nitrogen and potassium carbonate (592 mg) wasadded. The mixture was then stirred at room temperature for 1 hour,poured into water (50 mL), extracted into ethylacetate (3×50 mL), driedover anhydrous magnesium sulfate, filtered and concentrated to give thecrude product. This was purified by column chromatography eluting with2:1 iso-hexane/ethylacetate to give the epoxide (595 mg). (1S,2S)-(−)-N,N′-Bis(3,5-di-t-butylsalicydene)-1,2-cyclohexanediaminocobalt(II)(0.20 g), acetic acid (0.1 mL) and toluene (2 mL) were stirred togetherin air for 1.5 hours. The solvents were then removed in vacuo and theresultant brown glass was dried under high vacuum for 2 hours. Theepoxide described above (595 mg), water (1 mL) and tetrahydrofuran (30mL) were then added to this and the mixture stirred under nitrogen for92 hours, concentrated and purified by column chromatography elutingwith 2:1 isohexane/ethyl acetate to give the sub-titled compound (0.219g).

MS (ES+) ion [M+H]⁺ 360, 362

c)2-Chloro-5-[(2S)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,hydrochloride salt

2-Chloro-5-[(2S)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 13b) (110 mg), methylamine (40% aqueous solution, 2 mL) andtetrahydrofuran (10 mL) were heated together at 50° C. under nitrogenfor 20 hours, cooled and concentrated to give an oil. This was purifiedby Waters' MCX resin and then by column chromatography eluting with9:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolvedin dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) wasadded. The resulting white solid was filtered off to give the titledcompound (121 mg).

¹H NMR (400 MHz, d₆-DMSO) δ 8.29–8.26 (1H, t); 7.43–7.40 (1H, d);7.30–7.27 (2H, m); 5.55–5.53 (1H, d); 3.97 (1H, br m); 2.97–2.90 (3H,m); 2.80–2.67 (3H, m); 2.53 (3H, s); 1.94 (3H, br s); 1.69–1.58 (6H, brAB); 1.52 (6H, br s).

MS APCI(+ve) ion [M+H]⁺ 391, 393

m.p. 196° C.

EXAMPLE 14 2-Chloro-5-[(2S)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide, hydrochloride salt

2-Chloro-5-[(2S)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide(Example 13b) (110 mg), ethylamine (70% aqueous solution, 2 mL) andtetrahydrofuran (10 mL) were heated together at 50° C. under nitrogenfor 20 hours, cooled and concentrated to give an oil. This was purifiedby Waters' MCX resin and then by column chromatography eluting with9:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolvedin dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) wasadded. The resulting white solid was filtered off to give the titledcompound (109 mg).

¹H NMR (400 MHz, d₆-DMSO) δ 8.30–8.27 (1H, t); 7.43–7.40 (1H, d);7.30–7.28 (2H, m); 5.54–5.53 (1H, d); 3.99 (1H, br m); 3.00–2.87 (5H,m); 2.82–2.67 (3H, m); 1.94 (3H, br s); 1.69–1.58 (6H, br AB); 1.52 (6H,br s); 1.20–1.16 (3H, t).

MS APCI(+ve) ion [M+H]⁺ 405, 407

m.p. 214° C.

EXAMPLE 152-Chloro-5-[(2R)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,benzoic acid salt

a)2-Chloro-5-iodo-N-[(4-methoxyphenyl)methyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

Potassium t-butoxide (18.8 g) was added to a stirred solution of2-chloro-5-iodo-N-(tricyclo [3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide(prepared as described in WO 99/29661) (60.0 g) in anhydroustetrahydrofuran (600 mL) at 20° C. under nitrogen. After the additionwas complete, 4-methoxybenzyl chloride (20.8 mL) was added. The mixturewas heated to reflux for 12 hours and then cooled to room temperature.Water (600 mL) was added and the mixture extracted with dichloromethane(1.2 L then 400 mL). Organic extracts were dried over anhydrousmagnesium sulphate, filtered and evaporated under reduced pressure.

The residual solid was suspended in iso-hexane/t-butyl methyl ether(9:1, 1 L), stirred at reflux for 1 hour and then cooled to roomtemperature. The solid was filtered then dried in vacuo to give thesub-titled compound (72.88 g).

¹H NMR (400 MHz, CDCl₃) (major rotamer only) δ 1.62–1.77 (2H, m), 2.01(3H, s), 2.73 (1H, d), 3.71 (1H, d), 3.80 (3H, s), 4.38 (2H, ABq), 6.83(2H, d), 6.92 (2H, d),7.10 (1H, d), 7.42 (1H, d), 7.55 (1H, dd).

MS (APCI) ion [M+H]⁺ 550/552

b)2-Chloro-5-[(2S)-3-chloro-2-hydroxypropyl]-N-[(4-methoxyphenyl)methyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide

iso-Propylmagnesium chloride solution (2M in tetrahydrofuran, 72.9 mL)was added to a stirred solution of2-chloro-5-iodo-N-[(4-methoxyphenyl)methyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide (Example 15a) (72.87 g) inanhydrous tetrahydrofuran (1 L) at 0° C. under nitrogen. After 30minutes, copper(I) bromide dimethylsulphide complex (0.68 g) followed by(R)-(−)epichlorohydrin (11.4 mL) were added. The mixture was warmed to30° C. for 2 hours then diluted with saturated sodium bicarbonatesolution (1 L) and water (500 mL) then extracted with ethyl acetate (2×1L). Organic extracts were dried over anhydrous magnesium sulphate,filtered and evaporated under reduced pressure. The residual oil wasdissolved in methanol (600 mL), stirred overnight and the precipitatedsolid filtered and dried in vacuo to give the titled compound (52.25 g).

¹H NMR (400 MHz, CDCl₃) (major rotamer only) δ 1.50–1.78 (2H, m), 2.01(3H, s), 2.63 (1H, dd), 2.68–2.84 (2H, m), 3.24–3.30 (1H, m), 3.40 (1H,dt), 3.76–3.88 (5H, m), 4.40 (2H, ABq), 6.82 (2H, d), 6.95 (2H, d), 7.05(1H, d), 7.12 (1H, dd), 7.31 (1H, d).

MS (APCI) ion [M+H]⁺ 516/518/520

c)2-Chloro-5-[(2R)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)dec-1-ylmethyl)benzamide

A solution of2-chloro-5-[(2S)-3-chloro-2-hydroxypropyl]-N-[(4-methoxyphenyl)methyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide (Example 15b)) (52.24 g, 101mmol) in trifluoroacetic acid (260 mL) was heated at 50° C. for 16 hoursthen evaporated to a viscous oil. The oil was redissolved in methanol(500 mL) and evaporated in vacuo. The residual solid was dissolved intetrahydrofuran (300 mL) and a solution of sodium hydroxide (8.08 g) inmethanol (100 mL) was added. After 15 minutes, 40 wt % aqueousmethylamine solution (520 mL) was added. After 2 hours, the solution wasdecanted from a brown oil and evaporated under reduced pressure at 50°C. The resulting suspension was diluted with water (2 L), acidified topH<2 with 37 wt % hydrochloric acid, and extracted with ethyl acetate (1L). The organic layer was back-extracted with 0.5M hydrochloric acid (1L). Combined aqueous extracts were adjusted to pH 11–12 with 50 wt %sodium hydroxide solution, and extracted with ethyl acetate (2×1 L).Organic extracts were dried over anhydrous magnesium sulphate, filteredand evaporated under reduced pressure to give the titled compound as awhite solid (34.52 g).

¹H NMR (400 MHz, CDCl₃) δ 1.59 (6H, s), 1.65 (3H, d), 1.73 (3H, d), 2.01(3H, s), 2.42 (3H, s), 2.49 (1H, t), 2.68 (1H, dd), 2.71 (2H, d), 3.17(2H, d), 3.80–3.87 (1H, m), 6.29 (1H, s), 7.25 (1H, d), 7.33 (1H, d),7.58 (1H, s).

MS (APCI) ion [M+H]⁺ 510, 512

d)2-Chloro-5-[(2R)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamidebenzoic acid salt

Benzoic acid (11.07 g) was added to a suspension of2-chloro-5-[(2R)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide(Example 15c)) (33.54 g, 86 mmol) in 2-propanol (333 mL) and the mixtureheated to reflux whereupon a clear solution was obtained. t-Butyl methylether (1 L) was added dropwise over 30 minutes and the solutionmaintained at reflux. The solution was allowed to cool to roomtemperature, stirred for a further 2 hours and solid collected byfiltration, washed with t-butyl methyl ether and dried in vacuo at 40°C. to give the titled compound (24.5 g). The mother liquors wereevaporated in vacuo and the residue dissolved in 2-propanol (50 mL) atreflux, t-butyl methyl ether (150 mL) was added and a second crop wasisolated as before to give further titled compound (13 g).

¹H NMR (400 MHz, d₆-DMSO) δ 1.52 (6H, s), 1.59 (3H, d), 1.67 (3H, d),1.94 (3H, s), 2.43 (3H, s), 2.60–2.68 (2H, m), 2.72–2.79 (2H, m), 2.93(2H, d), 3.88–3.93 (1H, m), 7.26 (1H, s), 7.27 (1H, d), 7.35–7.40 (3H,m), 7.47 (1H, t), 7.90 (2H, d), 8.29 (1H, t).

MS (APCI) ion [M+H]⁺ 391, 393

Pharmacological Analysis

Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP)are known to be agonists of the P2X₇ receptor, effecting the formationof pores in the plasma membrane (Drug Development Research (1996),37(3), p.126). Consequently, when the receptor is activated using bbATPin the presence of ethidium bromide (a fluorescent DNA probe), anincrease in the fluorescence of intracellular DNA-bound ethidium bromideis observed. The increase in fluorescence can be used as a measure ofP2X₇ receptor activation and therefore to quantify the effect of acompound on the P2X₇ receptor.

In this manner, each of the title compounds of the Examples was testedfor antagonist activity at the P2X₇ receptor. Thus, the test wasperformed in 96-well flat bottomed microtitre plates, the wells beingfilled with 250 μl of test solution comprising 200 μl of a suspension ofTHP-1 cells (2.5×10⁶ cells/ml) containing 10⁻⁴M ethidium bromide, 25 μlof a high potassium buffer solution containing 10⁻⁵M bbATP, and 25 μl ofthe high potassium buffer solution containing 3×10⁻⁵M test compound. Theplate was covered with a plastics sheet and incubated at 37° C. for onehour. The plate was then read in a Perkin-Elmer fluorescent platereader, excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm, Em 20nm. For the purposes of comparison, bbATP (a P2X₇ receptor agonist) andpyridoxal 5-phosphate (a P2X₇ receptor antagonist) were used separatelyin the test as controls. From the readings obtained, a pIC₅₀ figure wascalculated for each test compound, this figure being the negativelogarithm of the concentration of test compound necessary to reduce thebbATP agonist activity by 50%. Each of the compounds of the Examplesdemonstrated antagonist activity, having a pIC₅₀ figure>4.50. Forexample, the compounds of Examples 1, 8 and 10 had pIC₅₀ values of 8.0,8.4 and 8.2 respectively.

1. A compound of formula

wherein m represents 1, 2 or 3; each R¹ independently represents ahydrogen or halogen atom; one of R² and R³ represents halogen, nitro,amino, hydroxyl, or a group selected from (i) C₁–C₆ alkyl optionallysubstituted by at least one halogen atom, (ii) C₃–C₈ cycloalkyl, (iii)C₁–C₆ alkoxy optionally substituted by at least one halogen atom, and(iv) C₃–C₈ cycloalkyloxy, and the other of R² and R³ represents ahydrogen or halogen atom; n represents 0, 1 or 2; and R⁴ and R⁵ eachindependently represent a hydrogen atom or a C₁–C₆ alkyl groupoptionally substituted by at least one substituent selected fromhydroxyl, halogen and C₁–C₆ alkoxy; or a pharmaceutically acceptablesalt or solvate thereof.
 2. A compound according to claim 1, wherein mis
 1. 3. A compound according to claim 1, wherein R³ represents ahydrogen atom.
 4. A compound according to claim 1, wherein n is
 1. 5. Acompound according to claim 4, which has the following stereochemistry:


6. A compound according to claim 1, wherein R⁴ and R⁵ each independentlyrepresent a hydrogen atom or a C₁–C₆ alkyl group optionally substitutedby at least one hydroxyl group.
 7. A compound according to claim 1,wherein m represents 1; each R¹ represents a hydrogen atom; one of R²and R³ represents a halogen atom, and the other of R² and R³ representsa hydrogen atom; n is 0, 1 or 2; and R⁴ and R⁵ each independentlyrepresent a hydrogen atom or a group selected from —CH₃, —C₂H₅,—CH(CH₃)₂ and —(CH₂)₃OH.
 8. A compound according to claim 1, wherein mrepresents 1; each R¹ represents a hydrogen atom; one of R² and R³represents a halogen atom, and the other of R² and R³ represents ahydrogen atom; n is 0, 1 or 2; and one of R⁴ and R⁵ represents ahydrogen atom or —CH₃ and the other of R⁴ and R⁵ represents a groupselected from —CH₃, —C₂H₅, —CH(CH₃)₂ and —(CH₂)₃OH.
 9. A compound beingselected from any one of:2-Chloro-5-[(3S)-3-hydroxy-4-(methylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,2-Chloro-5-[(3S)-3-hydroxy-4-(ethylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,2-Chloro-5-[(3S)-3-hydroxy-4-(1-methylethylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,2-Chloro-5-[(3R)-3-hydroxy-4-(methylamino)butyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,2-Chloro-5-[(2R)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamidehydrochloride,2-Chloro-5-[(2R)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,2-Chloro-5-[(2R)-2-hydroxy-3-[(1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamidehydrochloride,2-Chloro-5-[(2R)-2-hydroxy-3-[(1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,2-Chloro-5-[(2R)-2-hydroxy-3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamidehydrochloride,2-Chloro-5-[(2R)-2-hydroxy-3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,2-Chloro-5-[(2R)-3-(dimethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamidehydrochloride,2-Chloro-5-[(2R)-3-(dimethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,2-Chloro-5-[(1S)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamidehydrochloride,2-Chloro-5-[(1S)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,2-Chloro-5-[(1R)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamidehydrochloride,2-Chloro-5-[(1R)-1-hydroxy-2-(methylamino)ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,2-Chloro-5-[(1R)-2-(ethylamino)-1-hydroxyethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,2-Chloro-5-[(1R)-1-hydroxy-2-[(3-hydroxypropyl)amino]ethyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,2-Chloro-5-[(2S)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamidehydrochloride,2-Chloro-5-[(2S)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,2-Chloro-5-[(2S)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamidehydrochloride,2-Chloro-5-[(2S)-3-(ethylamino)-2-hydroxypropyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-benzamide,2-Chloro-5-[(2R)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamidebenzoic acid salt,2-Chloro-5-[(2R)-2-hydroxy-3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)benzamide,and all pharmaceutically acceptable salts and solvates thereof.
 10. Aprocess for the preparation of a compound according to claim 1, whichcomprises: (i) when n is 0, reacting a compound of formula

wherein m, R¹, R² and R³ are as defined in formula (I), with a compoundof formula (III), HNR⁴R⁵, wherein R⁴ and R⁵ are as defined in formula(I); or (ii) when n is 1, reacting a compound of formula

wherein m, R¹, R² and R³ are as defined in formula (I), with a compoundof formula (III) as defined in (i) above; or (iii) when n is 2, reactinga compound of formula

wherein L¹ is a leaving group and m, R¹, R² and R³ are as defined informula (I), with a compound of formula (III) as defined in (i) above;or (iv) when n is 1, reacting a compound of formula

wherein L² is a leaving group and m, R¹, R² and R³ are as defined informula (I), with a compound of formula (III) as defined in (i) above;and optionally after (i), (ii) (iii) or (iv) carrying out one or more ofthe following: converting the compound obtained to a further compound offormula (I) forming a pharmaceutically acceptable salt or solvate of thecompound.
 11. A pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof asclaimed in claim 1 in association with a pharmaceutically acceptableadjuvant, diluent or carrier.
 12. A process for the preparation of apharmaceutical composition which comprises mixing a compound of formula(I) or a pharmaceutically acceptable salt or solvate thereof as definedin claim 1 with a pharmaceutically acceptable adjuvant, diluent orcarrier.
 13. A method of treating rheumatoid arthritis or osteoarthritiswhich comprises administering to a patient a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof as claimed in claim
 1. 14. A method of treatingan obstructive airways disease which comprises administering to apatient a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof as claimed inclaim
 1. 15. The method of claim 14, wherein the obstructive airwaysdisease is asthma or chronic obstructive pulmonary disease.
 16. A methodof treating atherosclerosis which comprises administering to a patient atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as claimed in claim1.